rs55689103

chr7-103593755-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):c.3839G>A(p.Gly1280Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,988 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 33)
  • Exomes 𝑓: 0.015 (204 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.57

Genes affected

RELN (HGNC:9957): (reelin) This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.010104984).
• BP6: Variant 7-103593755-C-T is Benign according to our data. Variant chr7-103593755-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103593755-C-T is described in Lovd as [Likely_benign]. Variant chr7-103593755-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0114 (1738/152274) while in subpopulation AMR AF= 0.0214 (328/15298). AF 95% confidence interval is 0.0195. There are 13 homozygotes in gnomad4. There are 836 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.3839G>A	p.Gly1280Glu	missense_variant	27/65	ENST00000428762.6
RELN	NM_173054.3	c.3839G>A	p.Gly1280Glu	missense_variant	27/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.3839G>A	p.Gly1280Glu	missense_variant	27/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1738 AN: 152156 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0102 AC: 2563 AN: 251166 Hom.: 24 AF XY: 0.0102 AC XY: 1380 AN XY: 135744

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00966

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0149 AC: 21802 AN: 1461714 Hom.: 204 Cov.: 32 AF XY: 0.0144 AC XY: 10479 AN XY: 727154

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0114 AC: 1738 AN: 152274 Hom.: 13 Cov.: 33 AF XY: 0.0112 AC XY: 836 AN XY: 74450

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0147 Hom.: 19

Bravo AF: 0.0118

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0102 AC: 1238

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Norman-Roberts syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MPC		0.77
ClinPred		0.013	T
GERP RS		6.1
Varity_R		0.31
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55689103; hg19: chr7-103234202; COSMIC: COSV100635414;